beta-RA Targets Mitochondrial Metabolism and Adipogenesis, Leading to Therapeutic Benefits against CoQ Deficiency and Age-Related Overweight
| Autor: | Hidalgo Gutiérrez, Agustín, Barriocanal Casado, Eliana, Díaz Casado, María Elena, González García, Pilar, Acuña Castroviejo, Darío, López García, Luis Carlos |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
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| Zdroj: | Digibug. Repositorio Institucional de la Universidad de Granada instname |
| Popis: | This work was supported by grants from Ministerio de Ciencia e Innovacion, Spain, and the ERDF (grant number RTI2018-093503-B-100); from the Muscular Dystrophy Association (MDA602322); from the Junta de Andalucia (grant number P20_00134); from the University of Granada (grant reference "UNETE," UCE-PP2017-06); and by EPIC-XS, project number 823839, funded by the Horizon 2020 program of the European Union. P.G.-G. is a "FPU fellow" from the Ministerio de Universidades, Spain. M.E.D.-C. is supported by the Muscular Dystrophy Association. E.B.-C. is supported by the Junta de Andalucia. A.H.-G. was partially supported by the "FPU program" and the research program from the University of Granada. Primary mitochondrial diseases are caused by mutations in mitochondrial or nuclear genes, leading to the abnormal function of specific mitochondrial pathways. Mitochondrial dysfunction is also a secondary event in more common pathophysiological conditions, such as obesity and metabolic syndrome. In both cases, the improvement and management of mitochondrial homeostasis remain challenging. Here, we show that beta-resorcylic acid (beta-RA), which is a natural phenolic compound, competed in vivo with 4-hydroxybenzoic acid, which is the natural precursor of coenzyme Q biosynthesis. This led to a decrease in demethoxyubiquinone, which is an intermediate metabolite of CoQ biosynthesis that is abnormally accumulated in Coq9(R239X) mice. As a consequence, beta-RA rescued the phenotype of Coq9(R239X) mice, which is a model of primary mitochondrial encephalopathy. Moreover, we observed that long-term treatment with beta-RA also reduced the size and content of the white adipose tissue (WAT) that is normally accumulated during aging in wild-type mice, leading to the prevention of hepatic steatosis and an increase in survival at the elderly stage of life. The reduction in WAT content was due to a decrease in adipogenesis, an adaptation of the mitochondrial proteome in the kidneys, and stimulation of glycolysis and acetyl-CoA metabolism. Therefore, our results demonstrate that beta-RA acted through different cellular mechanisms, with effects on mitochondrial metabolism; as such, it may be used for the treatment of primary coenzyme Q deficiency, overweight, and hepatic steatosis. Spanish Government European Commission RTI2018-093503-B-100 Muscular Dystrophy Association MDA602322 Junta de Andalucia P20_00134 University of Granada UCE-PP2017-06 EPIC-XS - Horizon 2020 program of the European Union 823839 Muscular Dystrophy Association Junta de Andalucia University of Granada |
| Databáze: | OpenAIRE |
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